Determining which patients presenting with suspected acute infection require antibiotics is a common yet challenging medical decision. Clinical phenotypes widely overlap and current diagnostics are inadequate, leading all too commonly to a default decision to prescribe antibiotics. Consequently, antibiotic overuse and subsequent resistance have become major public health threats. Thus, there is a clear need for better strategies to safely reduce antibiotic overuse. A promising approach are strategies that combine therapeutics with novel diagnostics such as biomarkers to identify patients most likely to benefit from the therapeutic intervention. Landmark trials using this approach in oncology and cardiology have significantly improved routine practice. In infection and sepsis, based on extensive work by our group and others, we believe procalcitonin the biomarker most ready for a large US trial. Procalcitonin is a calcitonin precursor elevated in bacterial infection, but not viral. Multiple studies have shown procalcitonin has superior performance for detection of bacterial infection compared to traditional markers such as white blood cell count. We propose ProACT (Procalcitonin Antibiotic Consensus Trial), a 1514 subject, eight site, randomized trial to test implementation of a procalcitonin antibiotic algorithm to safely reduce antibiotic exposure in lower respiratory tract infection (LRTI). We target emergency department patients (ED) as a large proportion of LRTI presents to the ED, and although antibiotic prescription for respiratory infection in primary care has declined, this has not occurred in EDs. LRTI is a major public health burden and typifies the decision-making challenges of acute infection. Study findings will have an immediate impact on routine ED care of this common condition and could significantly reduce antibiotic use and resistance.